Journal
MOLECULAR PHARMACOLOGY
Volume 65, Issue 3, Pages 589-598Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.65.3.589
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The signaling pathway for IFN-gamma-mediated induction of ICAM-1 expression was further studied in human NCI-H292 epithelial cells. The Tyr701 phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by interferon-gamma (IFN-gamma) and 12-O-tetradecanoylphorbol 13-acetate (TPA) was inhibited by the protein kinase C (PKC) inhibitor staurosporine, the tyrosine kinase inhibitor herbimycin, or the Src kinase inhibitor PP2. An association between c-Src and STAT1 was increased by IFN-gamma and TPA, indicating the direct phosphorylation of STAT1 by PKC-dependent c-Src activation. Tyrosine phosphorylation of Janus kinases (JAK) 1/2 was induced by IFN-gamma but not by TPA. In addition, ICAM-1 promoter activity induced by IFN-gamma, but not that induced by TPA, was inhibited by the dominant-negative JAK1 and JAK2 mutants. IFN-gamma induced tyrosine phosphorylation of phospholipase C ( PLC)-gamma was inhibited by AG 490 ( a JAK inhibitor), and the association between JAK1/2 and PLC-gamma was increased after IFN-gamma treatment, indicating the activation of PLC-gamma via JAK1/2 phosphorylation. ICAM-1 promoter activities induced by the overexpression of wild-type JAK1- and PLC-gamma2 were blocked by the PLCgamma2 mutant or the dominant-negative PKCalpha (Lys-->Arg), c-Src (Lys-->Met), or STAT1 (Y701M) mutants, but not by dominant-negative STAT3 (DN) mutants. These results confirmed that IFN-gamma activated PLC-gamma via JAK1/2 phosphorylation to induce PKC, c-Src, STAT1 activation, and ICAM-1 expression. The association between JAK1/2 and STAT1 was increased by IFN-gamma but not by TPA. It was inhibited by AG 490 but not by U73122, indicating the possible involvement of the JAK1/2-STAT1 pathway. All the results show that IFN-gamma induces ICAM-1 expression by two different pathways in NCI-H292 epithelial cells. One is the JAK1/2-dependent PLC-gamma pathway inducing the activations of PKCalpha, c-Src, and STAT1, and the other is the direct activation of STAT1 by JAK1/2.
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